Abstract
Mammalian target of rapamycin (mTOR) inhibitors mediate AKT activation through a type I insulin‐like growth factor receptor (IGF‐1R)‐dependent mechanism, resulting in resistance to mTOR inhibition. Combining an mTOR inhibitor with an IGF‐1R antibody/inhibitor is expected to enhance mTORtargeted anticancer therapy. This NCI‐CTEP sponsored multicenter phase I clinical trial funded by R‐21 mechanism was aimed to define the maximum tolerated dose (MTD), biologic effects, and metabolic activity, individually and in combination, of IMC‐A12, a fully humanized IgG1 monoclonal antibody directed at the IGF‐IR, and temsirolimus, an inhibitor of mTOR.
Methods: A standard “3+3” design used a fixed dose of 25 mg IV weekly of temsirolimus with an escalating weekly dose of IV IMC‐A12 at 3, 4 and 6 mg/kg with no intrapatient dose escalation; 32 patients with advanced cancer (13 male, 19 female) were enrolled across 3 dose cohorts with the current dose cohort at 6 mg/kg weekly IV of IMC‐A12 and 25 mg weekly IV of temsirolimus. The MTD has not been reached. Two out of three patients with Ewing sarcoma had more than 20% tumor reduction. One patient with adenocortical carcinoma and one patient with Ewing sarcoma had stable disease for more than 6 months and are still receiving treatment.
Conclusions: Preliminary correlatives data show downregulation of pAKT and pS6K and suggest that the combination is well tolerated, warranting further investigation with dose escalation.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B61.
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